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Supplementation with α-ketoglutarate improved the efficacy of anti-PD1 melanoma treatment through epigenetic modulation of PD-L1

ABSTRACT: Patients with advanced melanoma have shown an improved outlook after receiving anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapy efficacy remains a major challenge. Here, our findings show significantly higher abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanomas via STAT1/3. We also found that supplementation with α-KG significantly increased methylcytosine dioxygenase TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 had been recognized and stabilized in PD-L1 promoter to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that the TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, we provide a novel insight into α-KG's function in melanoma anti-PD1 treatment and supplement of α-KG is a novel promising strategy to improve the efficacy of anti-PD1 therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE223110 | GEO | 2023/03/08

REPOSITORIES: GEO

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